Generation of heat in the range of temperature from about 40° C. to about 46° C. (hyperthermia) can cause irreversible damage to diseased cells, whereas normal cells are not similarly affected. Three widely investigated methods for inducing hyperthermia, including radio-frequency waves, magnetic fields and near infrared radiation, have been utilized. As mentioned in U.S. Pat. No. 7,074,175 to Handy, “Hyperthermia may hold promise as a treatment for cancer because it induces instantaneous necrosis (typically called thermo-ablation) and/or a heat-shock response in cells (classical hyperthermia), leading to cell death via a series of biochemical changes within the cell. State-of-the-art systems that employ radio-frequency (RF) hyperthermia, such as annular phased array systems (APAS), attempt to tune E-field energy for regional heating of deep-seated tumors. Such techniques are limited by the heterogeneities of tissue electrical conductivities and that of highly perfuse tissues, leading to the unsolved problems of ‘hot spot’ phenomena in unintended tissues with concomitant under dosage in the desired areas. These factors make selective heating of specific regions with such E-field dominant systems very difficult.”
As further mentioned by Handy et al., “Hyperthermia for cancer treatment using colloidal single domain magnetic suspensions (i.e., magnetic fluids) exposed to RF fields has been recognized for several decades. However, a major problem with magnetic fluid hyperthermia has been the inability to selectively deliver a lethal dose of particles to the tumor cells.” Nevertheless, these various approaches to cell-specific hyperthermia are active areas of research. Finally, it should be noted that, in some cases, heating of the local cell environment may be sufficient to kill the targeted cell but not sufficient to raise the temperature of the bulk medium.
Several laboratories have investigated cell-specific nanoparticle-based hyperthermia based on near infrared radiation (NIR). Research includes using techniques of NIR to excite gold nanoparticles and nanoshells as described in U.S. Pat. No. 6,530,944 to West et al. In the '944 patent, after nanoparticles are delivered to a tumor or nearby cancer cells, an external NIR laser of about 800 nm in wavelength is used to excite the gold shell (plasmon mode), to generate the necessary heat. The choice and design of core material shifts the natural plasmon resonance of the gold nanoshell from the 500 nm range (of solid gold nanoparticles) to the 800 nm range. A 800 nm NIR laser is used for optimal transmission through mammalian tissue due to “water windows” for NIR. The essentially energetically inert cores of these nanomaterials in the '944 patent are made of silica and gold sulfide, neither of which absorb x-rays in any significant amount. No example in the '944 patent discusses x-rays, except with respect to the diagnostic embodiments, in which the shell is doped with scintillator material. Such technical approaches are most likely to be effective for cells in a test tube or for surface tumors of the skin. However, NIR is of limited practical clinical value for most cancers because of the inability of safe amounts of NIR to penetrate more than a few centimeters into the human body. The '944 patent also discusses the use of scintillation probes that emit IR and NIR for imaging purposes, but there is no discussion of attempts at therapeutic heat treatment with such an approach.
Further work on evaluating NIR ablation of tumor cells with different types of gold (Au) and silver (Ag) nanoparticle structures has been reported by Chen et al., Nanotechnology 20(42), 425104/1-425104/9 2009. Three Au-based nanomaterials (silica core Au nanoshells, hollow Au/Ag nanospheres and Au nanorods) were evaluated for their comparative photothermal efficiencies at killing three types of malignant cells (A549 lung cancer cells, HeLa cervix cancer cells and TCC bladder cancer cells) using a continuous wave (CW) NIR laser. Photo destructive efficiency was evaluated as a function of the number of nanoparticles required to destroy the cancer cells under 808 nm laser wavelength at fixed laser power. Of the three nanomaterials, silica-core gold (Au) nanoshells needed the minimum number of particles to produce effective photo destruction, whereas gold nanorods needed the largest number of particles. Together with the calculated photothermal conversion efficiency, the photothermal efficiency rankings are silica-core Au nanoshells greater than hollow Au/Ag nanospheres greater than Au nanorods.
Delivering the nanoparticle to the vicinity of the targeted cell (“targeting”) is of critical importance. Beyond simply injecting the nanoparticles into a region of interest, there are a wide range of targeting methodologies involving tumor cell surface molecules, including the conjugation of antibodies to various therapeutic agents and drugs. The U. S. Food & Drug Administration (FDA) has approved a number of antibody-based cancer therapeutics. The ability to engineer antibodies, fragments, and peptides with altered properties such as antigen binding affinity, molecular architecture, specificity, and valence has enhanced their use in therapies. The advantages of antibody engineering have overcome the limitations of mouse monoclonal antibodies. Cancer immunotherapeutics have made use of advances in the chimerization and humanization of mouse antibodies to reduce immunogenic responses in humans. High affinity human antibodies have also been obtained from transgenic mice that contain many human immunoglobulin genes. In addition, phage display technology, ribosome display, and DNA shuffling have allowed for the discovery of antibody fragments and peptides that have the desirable properties of high affinity and low immunogenicity for use as targeting ligands. All of these advances have made it possible to design an immunotherapy that has a desired antigen binding affinity, specificity, and minimal immune response. In summary, there are several methods of targeting, including monoclonal antibodies (mABs) which are a practical way to carry a lethal agent specifically to the cancer cell and not to normal tissue.
The field of cancer immunotherapy makes use of markers that are expressed or over-expressed on cancer cells in comparison to normal cells. The identification of such markers is ongoing and the choice of a ligand/marker combination is critical to the success of any immunotherapy. Immunotherapy has fallen into several classes: (1) antibodies themselves that target growth receptors, disrupt cytokine pathways, or induce complement or antibody-dependent cytotoxicity; (2) direct arming of an antibody with a toxin, a radio nucleotide, or a cytokine; (3) indirect arming of an antibody by attachment to immunoliposomes used to deliver a toxin or by attachment to an immunological cell effectors (bispecific antibodies). Although armed antibodies have shown more potent tumor activity in clinical trials, there have been unacceptably high levels of toxicity. The disadvantage of therapies that rely on delivery of immunotoxins or radionucleotides (direct and indirect arming) has been that these agents are active at all times. There have been problems with damage to non-tumor cells and toxicity along with delivery challenges. Many immunotherapies have faced challenges with shed markers and delivery to the intended target. Cancer cells commonly shed antigen targets into the blood stream. Many antibody-based therapies are diluted by interaction with shed antigens. In addition, immune complexes can be formed between the immunotherapeutic and the shed antigen, which can lead to dose-limiting toxicities.
Therefore, the state-of-the-art regarding the use of nanoparticle-based cell-specific hyperthermia to treat most disease is such that nanoparticles can be delivered to the targeted cell, but these particles cannot be sufficiently heated to kill cells. The nanoparticles are not efficient producers of thermal energy with the energy sources and energy amounts supplied to them. New methods, involving new nanoparticle designs and energy sources, are needed to enable hyperthermia to be a practical and efficacious treatment method for disease.
It is therefore an object of the present invention to provide nanoparticles which are effective and efficient for use in hyperthermia treatment of diseases and disorders such as cancers, and which can be targeted for even greater specificity.